1. Direct cholinomimetic (Parasympathomimetics) Drugs
Prof. Alhaider 1435 H
College of Medicine
Department of Pharmacology

2. By the end of this lecture the student should know
Classification of nervous system.
Describe the various steps in cholinergic transmission.
Mention the different types, locations and actions of cholinergic receptors.
Describe the effects of acetylcholine on major organs
Classify cholinomimetic drugs.
Describe the kinetics, actions and uses of direct acting cholinomimetic drugs.

3. Nervous system Central nervous system Peripheral nervous system
Afferent Division
Efferent Division
Autonomic nervous
system
Somatic
system
Enteric nervous system
Parasympathetic nervous system
Sympathetic nervous system

4. Why Acetylcholine is very important neurotransmitter?
See the Next Figure

6. (craniosacral outflow)
Parasympathetic Nervous System
(craniosacral outflow)

8. Biosynthesis and pathway of Acetylcholine
(Cholinergic Transmission)

9. Cholinergic transmission

10. Cholinergic or parasympathetic receptors
Nicotinic (N, central) receptors.
Muscarinic (M, peripheral) receptors.
Central nicotinic receptor
Peripheral muscarinic receptor

11. Muscarinic receptors
Type II receptors : G-protein linked receptors
Located at all target organs that are innervated by parasympathetic fibers (e.g, heart, CVS, eye, bladder, etc).
Five subclasses exist (M1 - M5)
M1, M3, M5 are excitatory in function (stimulation).
M2, M4 are inhibitory in function (inhibition).

12. Pharmacological actions Locations Receptor
CNS excitation
Gastric acid secretion
Activation of phospholipase C  IP3 &DAG   Ca
CNS
Autonomic ganglia
gastric parietal cells
M1 (Neural)
Excitatory
Cardiac inhibition
Presynaptic inhibition
Inhibition of adenyl cyclase
( cAMP)
Opening of K channels
Heart
Presynaptic cholinergic fibers
M2 (Cardiac)
Inhibitory
Secretion of glands
Smooth muscle contraction
Vasodilatation (via NO)
Activation of phospholipase C 
IP3 & DAG.
Exocrine glands
Smooth muscles
Vascular endothelium M3
Glandular

13. Subtypes and characteristics of Cholinergic Receptors (Both the Muscarenic and Nicotinic)
Postrecptor mechanism
Structural features
Location
Other Name
Receptor type
IP3,DAG cascade
7 transmembrane segments,G protein linked
Nerves
M1a M1
Inhibition of cAMP production, activation of K channels
7 transmembrane segment,Gprotein-linked
Heart, nerves, smooth muscle
M2a,cardiac M2 M2
IP3,DAG casaded→cytosolic calcium →↑released
7 transmembrane segment ,G-protein linked
Glands,smooth muscle,endothelium
M2b glandular M2 M3
Inhibition of cAMP producation
7membrane segment Gprotein linked
? CNS m4
IP3 ,DAG,cascade
m51
Na+,K+depolarizing ion channel
Pentamer(αβδγ)2
Skeletal muscle neuromuscular junction
Muscle type,end plate receptor NM
αandβsubunitss only as α2β2α3β3
Postganglionic cell body,dendrites
Neuronal type , ganglion receptor NN

14. Nicotinic receptors Central cholinoceptor
Muscarinic receptors
Peripheral cholinoceptor
Nicotinic receptors
Central cholinoceptor
G protein linked receptors
Ion channel linked receptors
On all peripheral organs that receive postganglionic parasympathetic fibers
Autonomic ganglia (sympathetic & parasympathetic) stimulation ( Nn )
Heart (M2) inhibition
exocrine glands (M3) contraction
Adrenal medulla (Nn)
release of catecholamines
(Adrenaline & Noradrenaline)
Smooth muscles (GIT, urinary tract, bronchial muscles)
(M3) contraction
Skeletal muscle (Neuromuscular junction)
(Nm) Contraction
Excitatory or inhibitory
Almost excitatory

15. Type I receptors : ion channel linked receptors 1
Type I receptors : ion channel linked receptors 1. Autonomic ganglia (Nn). 2. Adrenal medulla (Nn). 3. CNS (Nn) 3.Neuromuscular junction (Nm)
Nicotinic receptors

16. Based on the receptor type, Acetylcholine has two main effects:
1) Cholinergic (cholinomimetics) actions
2) Nicotinic Actions

17. Nicotinic Actions Skeletal muscles: Low conc. muscle contraction
High conc.  persistent depolarization & paralysis.
Ganglia: stimulation of sympathetic & parasympathetic ganglia.
Adrenal medulla release of catecholamines (A & NA).
Nicotinic Actions

18. Muscarinic actions Cholinergic actions Organs
Contraction of circular muscle of iris (miosis)(M3)
Contraction of ciliary muscles for near vision (M3)
Eye
bradycardia ( heart rate ) (M2)
Release of NO (EDRF)
Heart
endothelium
Constriction of bronchial smooth muscles
Increase bronchial secretion M3
Lung
Increased peristalsis
Increased secretion
Contraction of sphincter M3
GIT
Contraction of muscles
Relaxation of sphincter M3
Urinary bladder
Increase of sweat, saliva, lacrimal, bronchial, intestinal secretions M3
Exocrine glands

20. Types of cholinomimetics (Parasympathomimetics)
Direct cholinomimetics
cause direct stimulation of cholinergic receptors.
Indirect cholinomimetics (anticholinesterases)
increase action of Ach indirectly by inhibiting acetylcholinesterase thus prevent the degradation of Ach (This will be the title of our lecture)

21. Features of Good Directly Acting Cholinergic Drugs
Since Ach is not specific and easily destroyed by Cholinesterase, thus it is very essential to obtain Cholinergic Drug that has low nicotinic activity, high muscarenic selectivity but with low susceptibility to cholinesterase. (See Figure)
Which drug that has such features?

22. Direct Cholinomimetics
1) Cholinesters (Quaternary)
Acetylcholine (M,N)
Carbachol (M,N)
Bethanechol (M)
2) Natural Alkaliods (Tertiary)
Pilocarpine (M)
Direct Cholinomimetics

25. Acetylcholine (Ach)
Muscarinic and nicotinic agonist
Not used clinically because Ach
Is not selective (N, M)
Has short duration of action. Why?
Due to rapid metabolism by acetycholinesterase

26. Synthetic choline esters
include drugs as bethanechol, carbachol
Quaternary ammonium compounds (polar)
Poor distribution
can not cross BBB (No CNS effects)
Not metabolized by cholinesterase.
Have longer duration of action than Ach.
Never given I.V. or I.M BUT S.C.

28. Carbachol
Orally-S.C.
Not metabolized by cholinesterases.
Longer duration of action than Ach
Muscarinic actions on Eye, GIT, UT. (Table
Has nicotinic actions (what are these actions?).
Used for
Mainly in glaucoma
Urinary retention & paralytic ileus (rarely used due to its nicotinic actions)

29. Bethanechol
Orally-SC
Prominent muscarinic actions on GIT, UT.
No nicotinic action
Not metabolized by cholinesterases.
Longer duration of action than Ach
Used for
In paralytic ileus
In urinary retention (in cases of post-operative atony, neurogenic bladder)

30. Pilocarpine
Natural alkaloids
Tertiary amine lipophilic
Pharmacokinetics
It is well absorbed
Good distribution
Cross BBB (has central effects).
Long duration of action
Direct muscarinic agonist
(mainly on eye & secretion).

31. better absorbed than Ach metabolized by cholinesterase
Pilocarpine
Bethanechol
Carbachol
ACh
Tertiary
non polar
Quaternary Polar
Chemistry
Complete
better absorbed than Ach
NOT
Absorption
metabolized by cholinesterase
Metabolism
by cholinesterase
Longer (++)
Very short
Duration
oral,
eye drops
Oral
S.C.
Oral,
I.V.
Administ.

32. Pilocarpine Bethanechol Carbachol ACh Muscarinic Nicotinic +++
Receptors
+++
More on eye, secretion
GIT, Urinary
bladder
Eye, GIT
Urinary bladder
NOT
Selectivity NO
Glaucoma
Xerostomia
Paralytic ileus
Urinary retention
Uses

33. Bethanechol Carbachol Pilocarpine ACh
Complete
NOT
Absorption
hydrolyzed by cholinesterase
NOT hydrolyzed by cholinesterase
Hydrolyzed by
cholinesterase
Metabolism
Longer (++)
Very short
Duration
Oral, S.C.
Oral,
eye drops
oral,
I.V.
Administ.

34. Bethanechol Carbachol Pilocarpine ACh Muscarinic Nicotinic +++
Receptors
+++
GIT, Urinary
bladder
Eye, GIT
Urinary bladder
More on eye, secretion
NOT
Selectivity NO
Urinary retention
Paralytic ileus
Glaucoma
Xerostomia
Uses

35. Cevimeline Direct acting muscarinic agonist at Glandular M3
Used orally for treatment of dry mouth symptom
associated with Sjogren's syndrome.

36. Contraindications of cholinomimetics
Bronchial asthma.
Peptic ulcer.
Angina pectoris
Intestinal obstruction
Incontinence

37. Practice for Home: What are the the naturally occuring alkaloids (e
Practice for Home: What are the the naturally occuring alkaloids (e.g: Pilocarpine and Oxotremorine and Muscarine) ? What is mushrooms poisoning? What are the differences between pilocarpine and bethanechol?.